Liver regeneration as treatment target for severe alcoholic hepatitis

Abstract

Severe alcoholic hepatitis (AH) is a distinct entity in the spectrum of alcohol-related liver disease, with limited treatment options and high mortality. Supportive medical care with corticosteroids in selected patients is the only currently available treatment option, often with poor outcomes. Based on the insights into the pathogenetic mechanisms of AH, which are mostly obtained from animal studies, several new treatment options are being explored. Studies have implicated impaired and deranged liver regeneration processes as one of the culprit mechanisms and a potential therapeutic target. Acknowledging evidence for the beneficial effects of granulocyte colony-stimulating factor (G-CSF) on liver regeneration and immunomodulation in animal models, several human studies investigated its role in the treatment of advanced alcohol-related liver disease and AH. Contrary to the previously published studies suggesting benefits of G-CSF in the outcomes of patients with severe AH, these effects were not confirmed by a recently published multicenter randomized trial, suggesting that other options should rather be pursued. Stem cell transplantation represents another option for improving liver regeneration, but evidence for its efficacy in patients with severe AH and advanced alcohol-related liver disease is still very scarce and unconvincing, with established lack of efficacy in patients with compensated cirrhosis. In this review, we summarize the current knowledge on the pathogenesis and experimental therapies targeting liver regeneration. The lack of high-quality studies and evidence is a major obstacle in further treatment development. New insights into the pathogenesis of not only liver injury, but also liver regeneration processes are mandatory for the development of new treatment options. A reliable experimental model of the pathogenesis of AH and processes involved in liver recovery is still missing, and data obtained from animal studies are essential for future research.

Keywords: Severe alcoholic hepatitis, Alcohol-related liver disease, Treatment, Liver regeneration, Granulocyte colony-stimulating factor, Stem cell transplantation

Core Tip: Current treatment options for patients with severe alcoholic hepatitis (AH) are unsatisfactory, resulting in high mortality rates. Liver regeneration is impaired in patients with severe AH and represents an appealing therapeutic target. Granulocyte-colony stimulating factor, alone or in combination with stem cell therapy represents a promising therapeutic option for severe AH. Contrary to animal and several small human studies, evidence from recent studies failed to show benefit of these liver regeneration therapies in patients with advanced alcohol related liver disease.